• Mayo Clinic proceedings · Feb 2025

    Body Fat Distribution and Ectopic Fat Accumulation as Mediator of Diabetogenic Action of Lipid-Modifying Drugs: A Mediation Mendelian Randomization Study.

    • Yuanlong Hu, Xinhai Cui, Mengkai Lu, Xiuya Guan, Yuan Li, Lei Zhang, Lin Lin, Zhiyuan Zhang, Muxin Zhang, Jiaqi Hao, Xiaojie Wang, Jiaming Huan, Yunlun Li, and Chao Li.
    • First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.
    • Mayo Clin. Proc. 2025 Feb 4.

    ObjectiveTo investigate the causal relationship between various lipid-modifying drugs and new-onset diabetes, as well as the mediators contributing to this relationship.MethodsMediation Mendelian randomization was performed to investigate the causal effect of lipid-modifying drug targets on type 2 diabetes (T2D) outcomes and the proportion of this association that is mediated through ectopic fat accumulation traits. Specific sets of variants in or near genes that encode 11 lipid-modifying drug targets (LDLR, HMGCR, NPC1L1, PCSK9, APOB, ABCG5/ABCG8, LPL, PPARA, ANGPTL3, APOC3, and CETP; for expansion of gene symbols, use search tool at www.genenames.org) were extracted. Random effects inverse variance weighted were performed to evaluate the causal effects among outcomes. Mediation analyses were performed to identify the mediators of the association between lipid-modifying drugs and T2D. The study was conducted from November 10, 2023, to April 2, 2024 RESULTS: The genetic mimicry of HMGCR and APOB inhibition was associated with an increased T2D risk, whereas the genetic mimicry of LPL enhancement was linked to a lower T2D risk. Gluteofemoral adipose tissue volume was a mediator for explaining 9.52% (P=.002), 16.90% (P=.03), and 10.50% (P=.003) of the total effect of HMGCR, APOB, and LPL on T2D susceptibility, respectively. Liver fat was a mediator for explaining 21.12% (P=.005), 12.28% (P=.03), and 9.84% (P=.005) of the total effect of HMGCR, APOB, and LPL on T2D susceptibility, respectively.ConclusionOur findings support the hypothesis that liver fat and gluteofemoral adipose tissue play a mediating role in the prodiabetic effects of HMGCR and APOB inhibition, as well as in the antidiabetic effects of LPL enhancement.Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

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